Vitamin D is a fat soluble vitamin that is found in food and is also made in the body after exposure to ultraviolet (UV) rays from the sun. Sunshine is a significant source of vitamin D because UV rays from sunlight trigger vitamin D synthesis in the skin. Vitamin D exists in several forms, each with a different level of activity. Vitamin D3 (cholecalciferol) is a non-activated form of vitamin D. It is a precursor of the hydroxylated, biologically active metabolites and analogues of vitamin D3. Generally cholecalciferol is activated by the liver via hydroxylation into 25-hydroxy-cholecalciferol. 25-hydroxy-cholecalciferol is further hydroxylated by the kidney at the 1-alpha-position to 1,25-dihydroxy-cholecalciferol (an active form of vitamin D3).
Vitamin D insufficiency is recognized as a cause of metabolic bone disease in adults that is characterized by the impairment of calcium and phosphate absorption. Vitamin D deficiency is also characterized by impaired bone mineralization. Sustained vitamin D insufficiency and deficiency are considered to be an important cause of gradual bone loss. Vitamin D3 (cholecalciferol) is implicated in numerous disorders. Cholecalciferol has been known to be intimately associated with regulation of calcium levels and bone metabolism and is implicated in osteomalacia, osteoporosis, osteopenia, fibrogenesis imperfecta ossium and rickets. Vitamin D3 increases calcium absorption from the gut and consequently plasma calcium, and suppresses secondary hyperparathyroidism and its skeletal consequences.
Cholecalciferol is known to be highly unstable. The major cause of this instability is its degradation particularly in the presence of oxygen and humidity. This lack of stability may often be detected as a drop in the level of cholecalciferol in a formulation. It has therefore been difficult to develop and market stable formulations of cholecalciferol.
Some attempts have been made to provide compositions of vitamin D3. PCT Publication WO2012/117236 discusses a pharmaceutical composition of at least 20,000 IU of vitamin D3 and a lipid based carrier excipient comprising an oil or mixture of oils in HPMC capsule. U.S. Pat. No. 5,804,573 discusses solid pharmaceutical compositions of active derivatives of vitamin D2 and vitamin D3 comprising at least one pharmaceutically acceptable antioxidant, a polyoxyalkyl stabilizer, and at least one solid pharmaceutical excipient or carrier. EP Patent Application 2201937A1 discloses a multiparticulate pharmaceutical delivery system of vitamin D or derivatives thereof comprising an inert core, an inner layer comprising vitamin D or derivative thereof, an emulsifier and an antioxidant, and an outer protective layer. U.S. Pat. No. 4,929,610 discusses pharmaceutical compositions wherein a pharmaceutical carrier is combined with a mixture of hydroxylated derivatives of vitamin D. In these compositions active substances are dissolved in a pharmaceutically usable solvent such as alcohol, propylene glycol, glycerine or polyethylene glycol and surface active agents are added therein. These mixtures are then filled in hard or soft gelatin capsules. WO03/059358 discloses an oil composition comprising 25-hydroxy vitamin D3 dissolved in the oil in an amount between 5% and 50% by weight of the total weight of the oil composition. This oil composition is then provided in the form of an emulsion, or microencapsulated oil, or a feed premix.
The above attempts, however, either use tedious processes for preparation of the compositions or provide liquid or oily compositions or are unlikely to remain stable over the shelf life of the product. Furthermore liquid or oil based formulations tend to be unstable or go rancid thereby affecting the potency as well as the taste of the product.
The present inventors after intensive research provide stabilized formulations of vitamin D, particularly vitamin D3 that remain stable over prolonged time periods even at accelerated storage conditions. The formulations of the present invention can further be employed to even provide high IU doses of the said vitamin without compromising on its stability and activity. The present inventors provide stable compositions of vitamin D3 without compromising on the desired release of the vitamin. The compositions of the present invention are prepared by simple cost-effective processes that provide the required homogeneity of distribution of vitamin D3 in the dosage form.
It is an object of the present invention to provide stabilized vitamin D formulations, and methods for preparing such formulations, or to at least provide the public with a useful choice.
In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.